Efficacy of the oral nucleoside prodrug GS-5245 (Obeldesivir) against SARS-CoV-2 and coronaviruses with pandemic potential

Abstract

Despite the wide availability of several safe and effective vaccines that can prevent severe COVID-19 disease, the emergence of SARS-CoV-2 variants of concern (VOC) that can partially evade vaccine immunity remains a global health concern. In addition, the emergence of highly mutated and neutralization-resistant SARS-CoV-2 VOCs such as BA.1 and BA.5 that can partially or fully evade (1) many therapeutic monoclonal antibodies in clinical use underlines the need for additional effective treatment strategies. Here, we characterize the antiviral activity of GS-5245, Obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved RNA-dependent viral RNA polymerase (RdRp). Importantly, we show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-related Bat-CoV RsSHC014, Middle East Respiratory Syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant in vitro and highly effective as antiviral therapy in mouse models of SARS-CoV, SARS-CoV-2 (WA/1), MERS-CoV and Bat-CoV RsSHC014 pathogenesis. In all these models of divergent coronaviruses, we observed protection and/or significant reduction of disease metrics such as weight loss, lung viral replication, acute lung injury, and degradation in pulmonary function in GS-5245-treated mice compared to vehicle controls. Finally, we demonstrate that GS-5245 in combination with the main protease (Mpro) inhibitor nirmatrelvir had increased efficacy in vivo against SARS-CoV-2 compared to each single agent. Altogether, our data supports the continuing clinical evaluation of GS-5245 in humans infected with COVID-19, including as part of a combination antiviral therapy, especially in populations with the most urgent need for more efficacious and durable interventions.

Discovery of C-Linked Nucleoside Analogues with Antiviral Activity against SARS-CoV-2

“…The corresponding 5′-ester prodrugs 12a and 12b , designed to improve oral absorption, were each dosed orally at 30 mg/kg. Obeldesivir ( 2 ) was previously reported to demonstrate efficacy in the mouse model at this oral dose level . Plasma levels of 10n were monitored for 24 h, and levels in liver and lung were also measured at 24 h postdosing (Table ).…”

“…Obeldesivir (2) was previously reported to demonstrate efficacy in the mouse model at this oral dose level. 63 Plasma levels of 10n were monitored for 24 h, and levels in liver and lung were also measured at 24 h postdosing (Table 5). IV dosing of 10n generated modest exposure in plasma with a large volume of distribution (38.8 L/kg), suggesting high tissue partitioning.…”

Enhanced broad spectrum in vitro antiviral efficacy of 3-F-4-MeO-Bn, 3-CN, and 4-CN derivatives of lipid remdesivir nucleoside monophosphate prodrugs

“…Several oral RDV prodrugs GS-5245 (ATV006, Obeldesivir), GS-621763, and VV116 are in various stages of clinical development for the treatment of SARS-CoV-2 ( Cao et al, 2022 ; Cao et al, 2023 ; Cox et al, 2021 ; Martinez et al, 2023 [preprint], Schäfer et al, 2022 ). GS-5245 and GS-621763 are rapidly metabolized to RVn (GS-441524) prior to cellular uptake in tissues, including the lung.…”

An Update on SARS-CoV-2 Clinical Trial Results—What We Can Learn for the Next Pandemic

“…However, it is important to note that with DAA, initiating treatment early whilst viral loads are high is crucial for compound efficacy ( Figure 2 ), and variable treatment windows may explain conflicting clinical trial results [ 17 ]. An oral pro-drug of remdesivir, obeldesivir, shows excellent cross-reactivity against multiple coronaviruses including MERS, in vitro [ 117 ]. A recent Phase 3 RCT to evaluate the efficacy and safety for the treatment of COVID-19 in non-hospitalised patients with a high risk for disease progression was discontinued due to lower than expected incidence rates and related hospitalisations or all-cause death, whilst a Phase 3 RCT in hospitalised patients is still ongoing [ 118 ].…”